Enhancement of bone morphogenetic protein-2-induced new bone formation in mice by the phosphodiesterase inhibitor pentoxifylline

Porous collagen disks (6 mm diameter, 1 mm thickness) were impregnated with recombinant human bone morphogenetic protein-2 (rhBMP-2) (5 mug/disk) and implanted onto the bark muscles of mice. Pentoxifylline (PTX), which is a m ethylxanthine-derived inhibitor of phosphodiesterases (PDEs), or vehicle, w as injected (5, 25, 50, 100, 200, and 300 mg/kg body weight/day) into the m ice subcutaneously once a day for 3 weeks from the day of implantation of t he bone morphogenetic protein (BMP)-laden disks. The rhBMP-2-induced ectopi c ossicles were harvested and examined using radiographic, histological, an d biochemical methods to determine size, bone quality, and calcium content. When compared with controls, ossicles from mice treated with >50 mg/kg per day of PTX were significantly larger in size and had a greater calcium con tent. However, no differences were noted in mice treated with lower doses ( 5 and 25 mg/kg per day) of PTX. The temporal sequence of the bone-forming p rocess was unchanged by PTX based on histological examination. The histolog y of the ossicles front high- and low-dose PTX-treated mice was essentially identical to that observed in the control mice. These experimental results indicate that PTX enhanced the bone-inducing capacity of BMP-2. The underl ying mechanism of action most likely involves the inhibition of intracellul ar phosphodiesterases and a resulting elevation of the intracellular conten t of cyclic nucleotides, Further studies are warranted to understand how BM P-induced bone formation is pharmacologically modified by PTX. (Bone 28:290 -294; 2001) (C) 2001 by Elsevier Science Inc. All rights reserved.